Extended sub-chronic exposure to heavy metal mixture induced multidrug resistance against chemotherapy agents in ovarian cancer cells

Abstract

Recent scientific findings suggest that persistent, minimal quantity exposure to heavy metals combinations can instigate negative reactions across various cell types, tissues, and organs. However, the interplay between heavy metals present in blood and cancerous cells remains largely unclear. We aimed to examine the capability of a Pb, Cd, and Co at very low concentrations blend to trigger multidrug resistance against chemotherapeutic remedies such as cisplatin, 5-fluorouracil, and doxorubicin in the NIH-Ovcar3 human ovarian cancer cell line. Additionally, we sought to dissect the molecular mechanisms bolstering this resistance. Our results illustrate that consistent administration of the heavy metal mixture at extraordinarily low concentrations fosters pronounced chemotherapy resistance in Ovcar3 cells via cross resistance. This resistance endured and was propagated through ensuing cell generations. We observed that ATP-binding cassette (ABC) membrane transporters, specifically P-gp/ABCB1, BRCP/ABCG2, and ABCC1-type cellular detoxification functions, were markedly overexpressed, playing a crucial role in multidrug resistance. This finding supports the molecular evidence of the acquired multidrug resistance phenotype and provides preliminary insights into the potential resistance mechanism. We also found decreased mortality rates in the resistant ovarian cancer cells, with the mitochondrial apoptosis pathway activating at a reduced rate post-chemotherapy relative to the non-resistant control cells. Furthermore, multidrug-resistant cells exhibited increased motility and enhanced wound-healing abilities, hinting at a higher metastatic potential. These findings suggest that analysing P-gp, BRCP, and ABCC1 multidrug resistance gene expression and/or protein levels within biopsy samples from ovarian cancer patients at risk of heavy metal exposure could prove advantageous in determining chemotherapy dosage and prolonging patient lifespan.